Process for preparation of prostaglandins

ABSTRACT

The resulting intermediate is subsequently fragmented to produce a further intermediate having stereochemistries such as are present in prostaglandins which, in turn, is converted by known techniques into prostaglandins.   IS SUBJECTED TO A PHOTOCHEMICAL CHEMICAL REACTION IN THE PRESENCE OF A PHOTOSENSITIZER WHEREBY TO EFFECT RING CLOSURE WITH THE CONVERSION TO A BICYCLO (2.1.1) SYSTEM FOLLOWED BY CONVERSION TO INTERMEDIATES SUCH AS   Preparation of prostaglandins and certain intermediates therefor wherein a 1,5-diene compound such as

Jan. 7, 1975 1 PROCESS FOR PREPARATION OF PROSTAGLANDINS [76] Inventor: Lawrence Libit, 240 E. OKeefe St,

Palo Alto, Calif. 94303 [22] Filed: Mar. 1, 1972 [21] Appl. No.: 230,939

[52] US. Cl 204/158 R [51] Int. Cl B01j 1/10 [58] Field of Search 204/158 R [56] References Cited UNITED STATES PATENTS 3,626,015 12/1971 Lewis et a1 204/158 R 3,660,260 5/1972 Schroeter 204/158 R Primary Examiner1-loward S. Williams Attorney, Agent, or Firm-Wallenstein, Spangenberg, Hattis & Strampel ABSTRACT Preparation of prostaglandins and certain intermediates therefor wherein a 1,5-diene compound such as is subjected to a photochemical chemical reaction in the presence of a photosensitizer whereby to effect ring closure with the conversion to a hicyclo [2.1.1] system followed by conversion to intermediates such OAc The resulting intermediate is subsequently fragmented to produce a further intermediate having stereochemistries such as are present in prostaglandins which, in turn, is converted by known techniques into prostaglandins.

4 Claims, No Drawings 1 2 PROCESS FOR PREPARATION OF volved the utilization of reactions which are difficult to PROSTAGLANDINS carry out even though, to at least a considerable extent,

glandins have the 20-carbon atom skeleton found in prostanoic acid. Many of the prostaglandins, and various methods for their preparation, are shownin one or more of US. Pat. Nos. 3,435,053; 3,505,386;

3,505,387; 3,524,867 and 3,598,858.

For illustrative purposes and by way of simplification of explanation of my invention, which is described below, two of the known prostaglandins are shown below in terms of their structural configuration:

they have utilized many classical synthetic procedures. lndeed, only recently has it apparently been possible to selectively introduce the aforesaid feature (d) into the molecule (E. J. Corey et al, J. Am. Chem. Soc., 92. 2586 (I970), and references cited therein).

My present invention results in materially simplifying the preparation of prostaglandins, in which all four of the aforementioned structural features are introduced. Furthermore, it results in the production ofa common key intermediate (3), shown below, from which all of the prostaglandins of the E and F series can be produced.

PGF (2) The so-called E type (i.e. E,) contains four significant structural features: (a) a B-hydroxy ketone, the hydroxyl having a specific stereochemical relationship to substituents at C-4 and 05; (b) a C carboxylic acid side chain that is cis to C-3 hydroxyl and trans to the C-5 allylic alcohol side chain; (c) an allylic alcohol side may have a d or 1 optical configuration, there are four (Dd; Dl; Ld; Ll) enantiomers of structure E The F type is a formal reduction product of the E series.

So far as I am aware, previously known synthetic routes to the preparation of prostaglandins, in their introduction of the aforementioned structural features into the prostaglandin molecules, have, in the main, in-

where R, and R are the same or different alkyl or cycloalkyl or aralkyl groups containing up to 8 carbon atoms, illustrative examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n amyl, isoamyl, n-hexyl, isohexyl, n-pentyl, isopentyl, n-octyl, isooctyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, or benzyl. it is particularly preferred that R, and R both be methyl. R is acyl, particularly lower monocarboxylic acyl such as acetyl, propionyl or butyryl but it can also be of aromatic or araliphatic character such as benzoyl or cyclohexylacetyl, particularly preferred being acetyl. Moreover, the OAc radical at the C position can be replaced by a CH X radical where X is halogen, notably chlorine or bromine. The integer w can range from I to 10, preferably being I.

In the practice of the process of my invention, the aforementioned intermediate (3) is produced and said intermediate is then transformed to prostaglandins of types E and F, all as is described below.

Before describing the particulars with respect to the process of my present invention, it may be pointed out that the aforementioned structural feature (a), (b) and (c) are achieved through the utilization of the aforesaid intermediate (3). The reactions pursuant to which the aforesaid structural features (a), (b) and (c) are introduced into the molecule are shown below:

(c)) HO OH o I S ll Where the intermediate is in the form of a compound correspond to geometric relationships present on the where the C-3 position is occupied by a CH -X radical five membered ring in the E type prostaglandins. In as aforesaid, then, upon reduction with a metal such as particular, the concerted ring opening of the epoxide in zinc, for instance, the'following reaction occurs, as il- 35 product (3a) produces the trans disubstituted double lustrated below I bond and the desired allylic C-l5 hydroxyl. Further- 2% 0 WIIC H S ll L H OH which shows the results of a variant form of the 1,4 more, the hydroxyl is produced with a single sense of fragmentation step. chirality (d or I), provided that product (3a) has been in view of the foregoing, it is clear that a base eataoptically resolved (the approach described here has a lyzed opening (or any 1,4 fragmentation reaction that provision for the specific introduction of two optical gives 4) of product (3a) produces product (4) (or its 55 centers with a single resolution). When the OH atformal acid hydrolysis product, intermediate product tached to the side chain at C-5 is formally oxidized to (5), which has configurations at C-l5, C-4 and OS that an acid, prostaglandin E is obtained as shown below:

(CiI-I 6- CO H ln'the following illustrative example of the production of intermediate compound (3), compound (6) is initially subjected to intramolecular photochemical cyclization by ultraviolet light in the presence of a photosensitizing agent as, for instance, benzophenone, as shown below:

tent or degree of the introduction of structural feature (d), namely, the control of optical activity at the G15 position. In other words. where a mixture of the (7a) and (7b) compounds is utilized, a dl mixture is created at the C-l5 position, whereas, if the mixture of (7a) and (71)) has been optically resolved (c.g. pure D or U.V. Light 0 Photosensitizer CH3 #2 C0) OAc CH O

The aforesaid intermediate (70) or (7b) is advantageously optically resolved into its d or 1 form by hydrolysis to its respective alcohol, followed by ester formation with an optically active acid and subsequent separation by procedures which are, per se, known to the art to produce predominately the (7a) or the (7b) compound, as the case may be. It is, however, unnecessary to make this separation since it bears only upon the ex- OAc l) cis. Wittig o 2) epoxidation cleavage cis Wittig epoxidation cleavage cis Wittig epoxidation cleavage trans Wittig epoxidation cleavage trans Wittig epoxlaation cleavage OAc lllLl lLDd lLLd

It is clear, from the foregoing, that, using compound (7b) (D or L), the same products are obtained (Dl, Ll, Dd, Ld) by means of the foregoing transformations provided 7b prefers the conformation shown below and epoxidations are anti to the acetate.

X H H c1 Elfa l i 6A2 Ozonolysis of compounds 70 and/or 7b is then carsaid compound 9a is then reacted with a hindered peracid, such as 2,6-dimethyl-3-chloroperbenzoic acid. The attack on the least hindered side of compound 9a occurs with the formation of epoxide compound 10a, as shown below:

(mel) In place of the acetate, other organic carboxylic acids ried out which results in the production of the correcan be used as, for instance, propionic acid, tert-butyl sponding aldehydes 8a and 8b, respectively as shown below:

OAc OAc OAc If desired, any mixture of aldehydes 8a and 8b can be equilibrated to produce essentially exclusively aldehyde 8a or aldehyde 8b, as the case may be. For purposes of discussion and convenience, reference is made below to the treatment of aldehyde 8a, except in references pertaining to structural feature (d).

The aldehyde 8a is next treated with a selective Wittig reagent to produce a cis or trans double bond, as desired, in accordance with known procedures E. J. Corey et al, J. Am. Chem. Soc., 91, 5675 (1969)). Where the cis disubstituted olefinic compound 9a is produced, as shown below,

Wittig Reagent that produces gig-disubstituted double bonds OAc OAc

carboxylic acid and benzoic acid.

Next, compound 10a (which is equivalent to intermediate compound 3) is base catalyzed fragmented to produce essentially the single isomer I la (intermediate 5), as shown below:

the G15 position. One can produce the same selectivnC H 1 OAc ity from a syn epoxide and front side displacement. 15

The conversion of compound 11a to prostaglandins (PGE for instance, starting with intermediate 3, the 0f the E and F Series is then Carried out in one Or following series of reactions can be carried out, utilizmore Of the manners desc fid bfi o ing procedural techniques which are, per se, known to In the case ,of the synthesis of prostaglandin E, h n;

H nC H o 5 11 l ll 0 ,o-Ac

a 1) Base H 2) Aczofi 0 I IIC H nC H OAc t ll r OH OH 'IsO HO OH 1) TsCl 9 HO OAc Pyridine v 0 S Il V y lK CO /CH OH T80 TsO OTI-IP OTHP i OH nC H 3 0 c H T OH 0 O n 5 11 S L/ L'(CH) col H+ H0 P SH3OH OTI-IP A OTHP n A O 5 l l PROCEDURE 1 Similarly, still another variation or modification of A Simple variant or difi ti f the Sequence in the sequence of Procedure 1 results in the production Procedure 1 results in the synthesis of PGE thusly: of 3- OTHP QTHP Selective Reduction of -C C HO C- (CH 3 (CH C0 H THPO OTHP 0 nC H 5 ll PGE 2 3 ,859, l 88 l3 l4 ca CH CEC-CH CH-PR C OAC OAc Electrophillic attack at double bond usually or acetylene introduced at later {I stage (CH2)6-CO2H OTHP Y 0 Procedure I 0\) Reactions CH CH selective hydrogenation, acetylene known to reduce faster than double bond (CH Z 2 6 (CH2)6 CO2H 0H H+ HO \OH OTHP CH3OH: 0 o

O A J v H i (20) PGE3 For the synthesis of the F series of prostaglandins, the The selective reduction of compound 2] can be following variation or modification of Procedure 1 reachieved by the introduction ofa large group at the C3 sults in the production of the prostaglandin F a: hydroxyl to create the most unfavorable 1,3 diaxial in- R 0 R2 O 1) selective reduction Selective r du tion 2) H OAc H0 3 l) TsCl 2 NaOH TsO I I HO I Q 13L- teraction in the molecule.

The reactions described in Procedure 1 and the variants and modifications thereof represent illustrative procedures, the aforedescribed photocyclization reaction and the 1,4-fragmentation reaction from a preferred conformation representing the essential procedures since these two reactions set up and produce the desired stereochemical relationships found in the prostaglandins. The conversion of the intermediate derived from the photocyclization 1,4-fragmentation reaction sequence involves simply the application of heretofore known reactions.

The above described intermediate 3 can be converted to prostaglandins by other procedures, per'se known to the art, as shown by the following series of reactions:

0 selective reduction diate 3 in the synthesis ofderivativcs thereof leading to the production of prostaglandins. The said examples are not to be construed as limitative of my invention since various other procedures can be utilized by the skilled chemist in the light of and based upon the teachings which I have provided. All parts given are by weight.

EXAMPLE Photocyclization of Intermediate 6. A solution of 10 parts of compound (6) and 5 parts of benzophenene in 1000 parts of pentane is irradiated (high pressure Hanovia Type L lamp fitted with a Pyrex filter) under argon at 05C for 10 hours. The solvent is removed at reduced pressure and the photocyclized product isolated by chromatography on silica gel. The resulting he O X 0. l 0 Q OAc 1) Base (NaOH) (or cyclopentanone) can be protected 0 5 ll j 5 11 K L a 0 0 OH 0 (Procedure I Reactions) PROCEDURE 2 Various modifications can be made from intermediate 3 to produce keto-aldehyde derivatives thereof which can, in turn, be converted by known procedures to various prostaglandins.

The following examples are illustrative of procedures, utilizing the foregoing teachings, for the production intermediate 3 and the utilization of said interme- Q Prostagl andin photocyclized product (7) is characterized by spectral analysis (lR, NMR and mass spectroscopy).

In summary, it will be seen that my present invention is concerned with a process for the synthesis of prostanoic acid derivatives, notably prostaglandins, in which the key features comprise l the photochemical ring closure of a 1,5-diene as illustrated below 0 OAC X I V U.V- Light 0 l) 3 2) Wittig (cis) 0 iz OAc base OAc to a bicyclo[2.l.l] system which is converted to key intermediate 3, a B-acetoxy-epoxide whose stereochemistry is controlled by the steric restraints present in the photoproduct (4); followed by (2), 1,3 fragmentation of the product which results in an intermediate whose stereochemistries are exactly those found in the prostaglandins of the E and F series. Optical resolution of photoproduct 4 can be effected, if desired, and when the resolved product is subjected to the said 1,3- fragmentation procedure, subsequent conversion is effected by known methods to the prostaglandins whereby pure (1 or 1 prostaglandins are selectively produced.

in the photochemical ring closure reaction, while benzophenone has been disclosed as a preferred photosensitizer in the reaction to produce intermediate compound 3, various other photosensitizers can be utilized.

1 claim:

1. In a process for the preparation of intermediates useful in the production of prostaglandins, the steps which comprise subjecting a compound corresponding to the formula R1 0 I H l/s tizing agent is benzophenone. 

1. IN A PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE PRODUCTION OF PROSTALGLANDINS, THE STEPS WHICH COMPRISE SUBJECTING A COMPOUND CORRESPONDING TO THE FORMULA
 2. The process of claim 1, in which R1 and R2 are each methyl and R3 is acetyl.
 3. The process of claim 2, in which the irradiation is effected By means of ultraviolet light.
 4. The process of claim 3, in which the photosensitizing agent is benzophenone. 